Traditional viral vaccines are normally developed by either creating attenuated viral strains for inoculation, such as the Sabine strain of poliovirus, or by injecting the patients with purified viral proteins such as employed in the hepatitis B vaccine. This method is highly efficacious, but is restricted to viruses with limited antigenic variance (either static or dynamic). Perhaps the best example of a virus where traditional vaccine approaches cannot be used is human rhinovirus. With more than 100 serotypes, development of attenuated variants is not feasible. Previous studies have identified the major antigenic sites on the exterior of the capsid proteins. However, these proteins cannot be expressed in a soluble form and none of the current neutralizing antibodies have been shown to recognize such mis-folded proteins. This proposal is aimed at creating pan-serotypic vaccines against viruses with highly variant antigenicity by targeting the portions of the capsid that undergo dynamic conformational changes, or 'breathing'. Over the past few years, we have shown that human rhinovirus transiently exposes buried portions of the capsid and that this process is crucial for the infection process. Further, we have shown that the region of the capsid exposed in this process is more conserved amongst the 100 serotypes than any other region of the virus. This could, therefore, represent the "Achilles''heel" of this highly diverse family of viruses and allow for a single, peptide-based vaccine that could ameliorate the common cold. Indeed, our preliminary evidence suggests that antiserum to such peptides does have pan-serotypic neutralizing activity. The goal here will be to combine structural biology, virology, and immunological methods to develop an efficacious vaccine for the common cold. If successful, the methods developed here will also yield a rapid way to identify potential, conserved, vaccine targets for other antigenically diverse viruses as well.